DMEAD: a new dialkyl azodicarboxylate for the Mitsunobu reaction

Article abstract of DOI:10.1016/j.tet.2009.05.048

Di-2-methoxyethyl azodicarboxylate (DMEAD) is prepared in 65% yield in two steps as a crystalline solid. Use of DMEAD in the Mitsunobu reaction of a variety of alcohols with pronucleophiles results in good yields of the products under sufficient stereospecificity of inversion, as conventional diisopropyl azodicarboxylate (DIAD) does. Isolation of the product is, however, much easier with DMEAD than that with DIAD, because the hydrazine produced from DMEAD is highly hydrophilic and is completely separable by a simple extraction into neutral water. Purification of the organic layer, after separation of the other by-product, triphenylphosphane oxide, by filtration, easily provides high purity of the product in a good yield. Concentration of the water layer yields the hydrazine, which can be reused for the preparation of DMEAD. One-step removal of the two by-products by the aqueous extraction was also possible when trimethylphosphane and DMEAD were employed.

Full text of DOI:10.1016/j.tet.2009.05.048

Tetrahedron 65 (2009) 6109–6114
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
DMEAD: a new dialkyl azodicarboxylate for the Mitsunobu reaction
*
Kazutake Hagiya, Natsuko Muramoto, Tomonori Misaki, Takashi Sugimura
Graduate School of Material Science, University of Hyogo, 3-2-1, Kohto, Kamigori, Ako-gun, Hyogo 678-1297, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 April 2009
Received in revised form 20 May 2009
Accepted 20 May 2009
Available online 27 May 2009
Di-2-methoxyethyl azodicarboxylate (DMEAD) is prepared in 65% yield in two steps as a crystalline solid.
Use of DMEAD in the Mitsunobu reaction of a variety of alcohols with pronucleophiles results in good
yields of the products under sufficient stereospecificity of inversion, as conventional diisopropyl azo-
dicarboxylate (DIAD) does. Isolation of the product is, however, much easier with DMEAD than that with
DIAD, because the hydrazine produced from DMEAD is highly hydrophilic and is completely separable by
a simple extraction into neutral water. Purification of the organic layer, after separation of the other by-
product, triphenylphosphane oxide, by filtration, easily provides high purity of the product in a good
yield. Concentration of the water layer yields the hydrazine, which can be reused for the preparation of
DMEAD. One-step removal of the two by-products by the aqueous extraction was also possible when
trimethylphosphane and DMEAD were employed.
Keywords:
Mitsunobu reagent
DAD
Separation-friendly reagent
Aqueous extraction
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
edicarboxylates are not so volatile to remove by evaporation, and
their chromatographic separation from the product is also difficult
Dialkyl azodicarboxylate esters (DADs) are electrophilic re-
agents that react with olefins as dienophiles to result in the [4þ2]
cycloadditions, or as enophiles to perform ene reactions.1 A more
important use of a DAD in organic synthesis is as one of the re-
agents in the Mitsunobu reaction, where cooperation of the oxi-
dative nature of DAD and the reducing nature of a phosphane
promotes dehydration between an alcohol and a carboxylic acid (or
one of other acidic pronucleophiles) to give an ester with complete
stereo-inversion at the alcoholic carbon.2 The reaction generally
proceeds smoothly at rt under almost neutral conditions using
a common DAD, the ethyl ester (DEAD) or the isopropyl ester
(DIAD), the latter of which is now more popular due to the stability
during storage and handling.
A major drawback of the Mitsunobu reaction is the formation of
two by-products, hydrazinedicarboxylate and phosphane oxide,
which must be removed from the reaction mixture to isolate a target
compound. The separation of the phosphane oxide is usually an in-
significantmatter, duetolowsolubilityoftheoxideproducedfromthe
commonlyemployed triphenylphosphane (¼triphenylphosphine). As
a matter of fact, concentration of the mixture of the Mitsunobu re-
action oftenprovides crystals of triphenylphosphane oxide, which can
be removed by filtration with a proper solvent such as petroleum
ether.
due to the moderate polarity. In addition, side-reactions of DAD
also produce moderately polar compounds. For those reasons, the
Mitsunobu reaction potentially involves difficulty in the isolation
process of the product.
To solve the separation problem, various modified reagents have
been developed.3 That is, DAD is supported on a polymer, and the
produced hydrazine is separated by filtration.4 An acidic,5,6 basic,7
or fluorous8,9 group is attached to a DAD, and the produced hydra-
zine is separated by extraction into a basic or acidic aqueous layer or
into a fluorous solvent, respectively. A DAD incorporating a proper
cyclic olefin can be polymerized by metathesis after the Mitsunobu
reaction.10 A particular hydrazine can be removed as a crystalline
product from the reaction mixture and can be reused for the prep-
aration of the DAD.11–13 Azodicarboxamides are also the reagents,
the hydrazines of which can be removed by the filtration14 or the
extraction,15 though their properties are somewhat different form
those of DAD. Use of DAD as a catalyst is also one of the solutions
because the amount of the produced hydrazine can be reduced.16
Even with the development of such DAD analogues, the classic
DEAD and DIAD are still major reagents in the Mitsunobu reactions,
due to the availability of the reagent. DEAD and DIAD are the sim-
plest DADs, but are already costly (e.g., 65 USD for 100 g of DIAD),
and their separation-friendly analogues are still more expensive.17
Here, we have studied a new approach to address the separation
problem by a molecular design to enable the separation of
a hydrazinedicarboxylate by extraction with neutral water. The
advantage of this reagent design is that both the hydrazine-free
product and impurity-free hydrazine can be obtained by simply the
extraction/concentration process. The former purity is important to
In contrast, the hydrazinedicarboxylate is problematic during the
separation of the product. Diethyl and diisopropyl hydrazin-
* Corresponding author. Tel.: þ81 791 58 0168; fax: þ81 791 58 0115.
E-mail address: sugimura@sci.u-hyogo.ac.jp (T. Sugimura).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.048

6110
K. Hagiya et al. / Tetrahedron 65 (2009) 6109–6114
achieve a separation-friendly or even a separation-free process, and
the latter purity affects the effectiveness of the reuse of the re-
covered hydrazine. The production cost is another key issue in the
reagent design. DIAD is cheaper than all other DAD analogues due
to their simple structure. However, the purification of DIAD as well
as DEAD, that are potentially explosive, necessitates distillation
under reduced pressure, and the total cost of a DAD production can
be reduced if the distillation is omitted. Di-2-methoxyethyl azodi-
carboxylate (DMEAD, 1) is our newly designed reagent that can be
produced by a commercially viable process, and its advantage as
a Mitsunobu reagent will be presented in this report (Fig. 1).18
DMEAD was synthesized from hydrazine 2 by several oxidation
methods,19 and found to be a crystalline compound. A reaction
with chlorine or sodium hypochlorite yielded DMEAD, but the
purity obtained after the extraction was not sufficiently high to
allow crystallization from the reaction mixture. The oxidation
with NBS in the presence of pyridine in toluene produced less
side-products, and the reaction mixture after the extraction/dry-
ing/concentration process was crystallized in a mixture of toluene
and hexane to give pure DMEAD in 85% yield as yellow prisms (mp
39.9–40.4 ꢀC).
The thermal stability of DMEAD was evaluated by the de-
composition temperature. By the differential scanning calorime-
try (DSC) measurement, DMEAD was found to decompose at
210 ꢀC (927 J/g, exothermic), while DEAD and DIAD decomposed
at 227 ꢀC (1088 J/g) and 249 ꢀC (999 J/g), respectively. The lower
decomposition temperature of DMEAD indicates less stability at
high temperatures, but at room temperature, the crystalline
DMEAD must have an advantage in the stability relative to the
liquid DEAD and DIAD. As a matter of fact, DMEAD maintained
its crystalline form for more than three months at rt and over
a year at 5 ꢀC.
O
O
N
O
N
O
N
O
N
O
O
O
DEAD
O
DIAD
O
O
N
O
N
O
O
DMEAD (1)
2.2. Mitsunobu reaction with reagent recycles
Figure 1. DEAD and DIAD, the classic DAD analogues, and DMEAD (1), the new
analogue.
The recovery process of both the by-products of the Mitsunobu
reaction was demonstrated by using DMEAD. Optically active (S)-2-
octanol (2 g) of 96% enantiomeric excess (ee) was converted to (R)-
2-benzoyloxyoctane (3a) by the reaction with 1.1 molar amounts
each of benzoic acid, triphenylphosphane, and DMEAD in diethyl
ether (120 mL) at rt. Consumption of the reagents proceeded
smoothly, and the reaction was completed within 2 h. The reaction
mixture was washed with water, and the aqueous layer obtained
was re-extracted with diethyl ether (Fig. 2). The aqueous layer then
contained only the hydrazine 2 (>98% pure by 1H NMR) in 94% yield
based on the employed amount of DMEAD, which is 100% of the
theoretical value. Recovery of sufficiently pure 2 to reuse was ac-
complished by a single recrystallization from a mixture of acetone
and toluene in 75% yield.
2. Results and discussion
2.1. Preparation and physical properties of DMEAD
Di-2-methoxyethyl hydrazinedicarboxylate (2) was prepared by
mixing commercially available reagents, hydrazine hydrate, 2-
methoxyethyl chloroformate, and sodium carbonate in aqueous
ethanol in 76% yield after recrystallization (Scheme 1). The hydra-
zine 2 is a precursor of DMEAD but also the by-product of the Mit-
sunobu reaction with DMEAD; therefore, the properties of 2 are of
importance for the separation and recycling process. The solubility
of 2 is very poor (<0.01 g/mL, rt) in ether or toluene, moderately
high in ethyl acetate (0.1) and chloroform (0.25) and very high in
water (0.55). The solubility in water is better than that of the methyl
analogue (0.15) and much better than those of the ethyl and iso-
propyl analogues (<0.01), which are the hydrazines formed from
DEAD and DIAD, respectively. The partition coefficient Kd of 2 at
23 ꢀC was 0.045 for ether/water and 0.025 for toluene/water. From
these properties, it was expected that 2 of the by-product in the
Mitsunobu reaction with DMEAD could be removed from the
reaction mixture by a simple extraction.
OH
+
+
+
DMEAD
PPh3
PhCOOH
(1.1 equiv)
(1.1 equiv)
(1.1 equiv)
in ether (THF) at rt
OBz
O
Et2O, H2O
Na2CO3
+
+
hydrazine 2
O PPh3
N2H4·H2O
O
+
O
Cl
3a
extraction with water
water layer
O
H
organic layer
OBz
NBS
pyridine
N
O
O
O
DMEAD (1)
(85%)
O
N
H
O
+
hydrazine 2
75% yield
O PPh3
3a
2 (76%)
Scheme 1. Preparation of DMEAD (1).
filtration
(after recrystallization)
with hexane
filtrate
OBz
solid
The Rf value of 2 on a silica gel TLC plate was very small, 0.08
(elution with a mixture of ethyl acetate and hexane¼1/1) compared
with the ethyl (Rf¼0.44) or the isopropyl analogue (0.65) and is
sufficiently smaller than common carboxylic esters (>0.5) of the
Mitsunobu product. The high polarity of 2 promised an easy and
complete separation of the product by column chromatography.
O PPh3
79% yield
(crude)
89% yield
(after column)
Figure 2. Separation process of the Mitsunobu reaction using DMEAD.

K. Hagiya et al. / Tetrahedron 65 (2009) 6109–6114
6111
The organic layer was dried, concentrated, and suspended in
hexane. Unreacted triphenylphosphane was consumed during this
process, and most of the phosphane oxide was recovered by fil-
tration of the suspension in a crystalline form at 79% based on the
employed amount of triphenylphosphane (>90% pure by 1H NMR).
Some side-products produced from DMEAD were also included in
the crystalline part. The filtrate consisted mostly of 3a, ca. 80% (mol/
mol), with accompanying some triphenylphosphane oxide and
a trace amount of 2 deduced from the 1H NMR. Application of the
mixture to a short silica gel column afforded chemically pure (R)-3a
in 89% yield.
The same conversion was also demonstrated in THF, another
popular solvent for the Mitsunobu reaction having higher dissolv-
ing power. The reactivity was similar to that in diethyl ether, and by
the same procedure, except for exchange of the solvent to toluene
prior to the extraction, 2 was recovered in 71% yield after re-
crystallization. The product was also isolated in 83% yield after
chromatography. During the reactions both in diethyl ether and
THF, the complete stereochemical inversion was confirmed by
chiral HPLC analysis as well as the optical rotation of 3a.
occurred at the benzylic position in the polar media should be at-
tributable to the SN1 mechanism.20
2.4. Reaction with different pronucleophiles
(efficiency of product isolation)
The difference between DMEAD and DIAD in the Mitsunobu re-
action was further studied with a symmetric diol, where a selectivity
of the reaction is required for the mono-derivation. Stereochemically
pure (2R,4R)-2,4-pentanediol (>99% de and ee) was employed, and
thus, the stereospecificity of the reaction could be verified as a di-
astereomeric purity of the product (Table 2). Pronucleophiles having
different acidity in a pKa range between 3.4 and 10.2 were tested
because the acidity is a key issue for efficiency of the Mitsunobu
reaction.2,22 In addition, this series of experiments indicate a usabil-
ity of DMEAD in the Mitsunobu reaction because the expected
products having a remaining hydroxy group are properly polar in
different degree, and are considered to be good models to test the
efficiency of the product separation from a moderately polar
hydrazinedicarboxylate by the conventional chromatography.
2.3. Stereospecificity with DMEAD
Table 2
Selective mono-derivation of 2,4-pentanediol with varied pronucleophilesa
Stereospecific inversion of the Mitsunobu reaction is usually
observed, but in some cases, the reaction accompanies an SN1
process20 or the retention process via the acyloxy phosphonium
ion.21 The stereospecificity of the reaction with DMEAD was studied
using different reaction solvents and two optically active sub-
strates, (S)-2-octanol (96% ee) and (S)-1-phenylethylalcohol (98%
ee). Through this series, 4-nitrobenzoic acid was used as a nucleo-
phile (Table 1). Some reactions were also performed with DIAD; the
results are shown in parentheses.
O
HO
R
R
R = NO2
OH O
R = H
O
DMEAD or DIAD
HO
OH OH PPh3 in THF, rt
R'
OH O
R' = COOMe
R' = H
R'
R' = OMe
No.
Nu–H (pKa)
Yield/% (diester/%)
DMEAD
Table 1
DIADb
Stereospecificity in the reaction of optically active alcohols with DMEAD (or DIAD,
shown in parentheses) and PPh3
a
1
2
3
4
5
6
4-Nitrobenzoic acid (3.44)
4-Nitrobenzoic acid (3.44)
Benzoic acid (4.20)
4-Methoxycarbonylphenol (8.74)
Phenol (9.95)
45 (26)
79 (<5)
74 (<5)
83 (<5)
84 (<5)
82 (<5)
40 (30)
83 (<5)
74 (<5)
91 (<5)
80 (<5)
83 (<5)
OH
R
ArCOO
rt
+
p-NO2C6H4COOH
R
R = hexyl (96% ee)
R = Ph (98% ee)
3b. R = hexyl
4b. R = Ph
4-Methoxyphenol (10.20)
ee/%b
a
Entry
R
Solvent
Time/h
Yield/%
All reactions were carried out at rt in THF by addition of DAD to the mixture of
the other reactions in a ratio of diol/pronucleophile/DAD/PPh3¼1.2/1/1.2/1.2. For
1
2
3
4
5
6
7
8
C6H13
C6H13
C6H13
C6H13
Ph
Ph
Ph
Ph
Toluene
CH2Cl2
THF
CH3CN
Toluene
CH2Cl2
THF
3.5
1.5
2.5 (2)
21
6 (5)
46
96
89
90 (96)
54
91 (90)
74
96
96
96 (96)
95
95 (97)
86
entry 2, 4-nitrobenzoic acid was added to the mixture of the other three reagents.
b
Estimated yield based on 1H NMR.
The reactions shown in Table 2 were carried out in THF at rt by
addition of DMEAD or DIAD to a mixture of the other three com-
ponents except for entry 2, where the acid was added to a mixture of
the others. The reagent ratio was fixed at diol/pronucleophile/
4 (4)
40
84 (89)
30
80 (80)
54
CH3CN
a
All reactions were carried out at rt in a reagent ratio of alcohol/pronucleophile/
DMEAD/PPh3¼1/1.2/1.2/1.2.
b
DMEAD(DIAD)/PPh3¼1.2/1/1.2/1.2.
A sufficiently acidic 4-nitro-
Determined by HPLC.
benzoic acid is a popular pronucleophile in the Mitsunobu reaction,
but in the present case, bis-derivation occurred considerably to give
the diester in 26%, and low mono-derivation selectivity (45%) was
observed (entry 1). The low mono-selectivity was also observed with
DIAD. However, modification of the addition method to reduce the
concentration of the acid during the reaction resulted in selective
mono-derivation (entry 2). The reactions with the other pronu-
cleophiles are selective by the regular addition method, resulting in
only 2–3% of the diesters (entries 3–6). The high mono-derivation
selectivity of the 1,3-diol may suggest the formation of a cyclic
phosphorane intermediate with the diol. Actually, the reagents were
mostly consumed without addition of the pronucleophile deduced
from disappearance of the yellow solution color. The phosphorane
intermediate should be converted to the phosphonium precursor for
the product by the proton transfer from the pronucleophile.
The reactions with 2-octanol occurred smoothly except in ace-
tonitrile (entry 4), and ester 3b was obtained under complete ste-
reochemical inversion (entries 1–3). In contrast, the reaction of (S)-
1-phenylethanol resulted in a loss of the original stereochemical
purity in all the solvents during the conversion to 4b.2d The degree of
the loss was strongly dependent on the solvent polarity; 3% loss in
toluene (entry 5) but 44% loss in acetonitrile (entry 8). Comparing
with DIAD, isolated yields in THF are slightly lower (entries 3 and 7),
which might be improved by the optimization of the reaction con-
ditions. A drawback of DMEAD is seen in the reaction in toluene
(entry 5). DMEAD and its hydrazine increase the polarity of the re-
action media to reduce the stereospecificity in 3%, which is larger
than that with DIAD (1%). The observed imperfect stereo-inversion

6112
K. Hagiya et al. / Tetrahedron 65 (2009) 6109–6114
The product mono-alcohols have moderately low Rf values (0.4–
the reaction with 2-octanol was unsatisfactory in the yield of the 2-
octyl tosylamide both with DIAD and DMEAD (entry 4). Intra-
molecular reaction to give a macrolactone is not high yielding for
the Mitsunobu reaction. As a matter of fact, the cyclization of the
16-membered ring resulted in only a moderate yield in the re-
actions with both DMEAD and DIAD (entry 5).
0.6 with ethyl acetate/hexane¼3/7 to 6/4) on silica gel TLC, and for
the same reactions with DIAD, complete separations of the prod-
ucts from the diisopropyl hydrazinedicarboxylate were not possible
(except for the reaction in entry 5), but the hydrazine was con-
taminated in a considerable amount (25–35% of the product) after
the silica gel chromatography. These results are contrasting to the
easy isolations demonstrated with DMEAD, and it is clearly an
advantage of DMEAD in the Mitsunobu reaction. Stereospecificity
was also very high with both reagents to give >98% diastereomeric
excess of the products in all cases.
2.6. Total separation by aqueous workup
Triphenylphosphane oxide of the other by-product can be
removed by the precipitation/filtration process, but this process
could not remove all the oxide from the reaction mixture. In
addition, total removal of both the by-products by a simple
aqueous workup is sometimes preferable; especially when the
reaction scale is not so large. To realize this in the Mitsunobu
reaction with DMEAD, trimethylphosphane (TMP) was selected
because its oxide is known to be removable by the aqueous
workup.23 TMP is a less popular phosphane in the Mitsunobu
reaction, and may have a difficulty in its use other than the price.
Comparing with conventional triphenylphosphane, the phos-
phorous atom in TMP is less hindered and more basic (pKBHþ of
PMe3¼8.65, PPh3¼2.73), and thus TMP should have stronger
nucleophilicity and reducing power. TMP has been employed
with the combination of less oxidative urea type DAD (e.g., 1,10-
(azodicarbonyl)dipiperidine), and this combination is effective
for the Mitsunobu reaction with reductive substrates such as
thiol.24 In the case of the combination with DMEAD, the Mitsu-
nobu reaction was sluggish to result in less than 20% conversion,
presumably due to the too stable nature of the reagents complex.
By tuning the reaction conditions, the reaction at 60 ꢀC in toluene
was found to result in the high conversion in 12 h. After cooling,
the reaction mixture was washed with water (two times), dried,
and concentrated under vacuum to give a crude product, which
contained no trace TMP nor its oxide. From the reaction of (S)-2-
octanol (96% ee) with benzoic acid in a reagent ratio of 2-octanol/
benzoic acid/DMEAD/PMe3¼1/1/1.3/1.3, 3a was obtained in 82%
yield after the column chromatographic purification. The stereo-
inversion was almost perfect to yield 95% ee of (R)-3a. Under the
same conditions, (S)-1-phenylethylalcohol (98% ee) was con-
verted to the benzoate analogue 4a in 82% yield (96% ee). It
should be noted that the same reaction except use of p-nitro-
benzoic acid instead of benzoic acid resulted in poor results in
both the conversion (75% in 18 h) and the inversion (80% ee) to
give the low isolated yield (57%). The imperfect stereo-inversion
may be caused by the reaction with the acyloxy phosphonium
ion and the alcohol.21 Although the DMEAD/TMP combination is
effective to isolate the product by a simple extraction, the ap-
plicable range is not so clear yet.
2.5. Further study on applicability of DMEAD
The performance of DMEAD in the Mitsunobu reaction was
further tested for different combinations of alcohols and pronu-
cleophiles, in comparison with that of DIAD. The reactions were
carried out in THF at rt with 1.2 molar amounts of the reagents. The
results are given in Table 3. Menthol is a less reactive substrate but
could be converted to the diastereomerically pure isomenthol ester
with 4-nitrobenzoic acid in a good yield, though the reaction took
a longer time, similarly to the same reaction with DIAD (entry 1).
Phthalimide, a nitrogen pronucleophile, reacted smoothly with
a primary alcohol with DMEAD to give the corresponding imide,
while the reaction with DIAD proceeded more slowly and resulted
in incomplete consumption of the alcohol in the longer reaction
time under the present conditions (entry 2). The reaction of 1-
methyl-1H-tetrazole-5-thiol with glycolic acid methyl ester yielded
tetrazolylsulfanyl acetate in 88% yield after short column chroma-
tography on silica gel. For this conversion, use of DIAD caused
a problem in the separation of the by-product hydrazine from the
product by silica gel column chromatography (entry 3). N-Methyl-
tosylamide is a potent nucleophile in the Mitsunobu reaction, but
Table 3
Different combinations of the pronucleophile and alcohola
No.
Alcohol
Nu–H
DMEAD
DIAD
Time/h Yield/% Time/h Yield/%
OH
COOH
1
17
73
94
17
4
72
67
O2N
O
HO
HO
2
2.5
NH
O
N
N
N
O
3
4
2
88
33
3
65b
3. Conclusions
SH
N
OMe
H
N
In this report, we have shown that the hydrazine formed during
the Mitsunobu reaction with DMEAD could be effectively removed
by a simple extraction with neutral water from the reaction mixture
and is recovered in sufficiently pure form for reuse. The production
cost of DMEAD is clearly less than that of the other alternatives so
far reported to solve the separation problem. Compared with con-
ventional DIAD, DMEAD may cost more due to the use of 2-
methoxyethyl chloroformate in place of isopropyl chloroformate,
but DMEAD has an advantage over DIAD (DEAD) due to the easy
purification step (no distillation) that can overcome the cost of the
raw materials. DMEAD can be used in the Mitsunobu reaction in
almost the same way as DIAD but is a much more preferable re-
agent that allows easy separation and reagent-reusable processes.
DMEAD is now obtainable from a commercial source.
O
OH
Hex
21
15
55 (53)c
S
O
O
OH
5
12.5
31
19
38
HO
a
All reactions were carried out at rt in THF with the reagents in a ratio of alcohol/
pronucleophile/DMEAD or DIAD/PPh3¼1/1.2/1.2/1.2.
b
The product obtained by the SiO2 chromatography in 97% crude yield contained
32% (w/w) of the hydrazine.
c
Reported yield with DEAD.

K. Hagiya et al. / Tetrahedron 65 (2009) 6109–6114
6113
4. Experimental section
4.1. General
a mixture of acetone/toluene (¼5/8) to give 3.01 g of 2 as a colorless
powder. The organic layer was washed with water (100 mL), brine
(100 mL), dried over magnesium sulfate, concentrated, and sus-
pended in hexane (100 mL). Filtration of the suspension afforded
triphenylphosphane oxide as a colorless solid (3.69 g). The filtrate
was concentrated and purified by a short column on silica gel (elution
with 5% ethyl acetate in hexane) to give 3.18 g of 3a as a colorless
2-Methoxyethyl chloroformate was obtained from Tokyo
Chemical Industry Co., Ltd. Substrate in Table 3, entry 5 was
obtained by the hydrolysis of the lactone. The other chemicals were
obtained from commercial sources. All anhydrous reactions were
performed under nitrogen in flame-dried glassware using solvents
distilled over proper drying agents. Melting points were obtained
on a BUHCI Melting Point B-545. All products were characterized by
NMR spectrometry using a JEOL ECA-600 spectrometer or a JEOL
AL-400 at 400 MHz, and by IR with a SHIMAZU IR Prestige-21.
Optical rotations were measured on a Perkin–Elmer 241 polarimeter.
Elemental analyses were performed with a Perkin–Elmer CHNS/O
Analyzer 2400. High resolution MS was obtained with a JEOL JMS-
AX505-HA. Enantiomeric purities were determined by HPLC anal-
ysis using a chiral column (DAICEL CHIRALPAK AD for 3a and
CHIRALCEL OJ-H for the others).
20
20
liquid (89% yield). [
0.032, THF).
a
]
ꢁ40.6 (c 1.06, MeOH). Lit.25
[a]
ꢁ39.5 (c
D
D
4.5. The reaction of (S)-2-octanol and benzoic acid in THF
To a solution of (S)-2-octanol (2 g, 15.4 mmol), benzoic acid
(2.06 g, 16.9 mmol), and triphenylphosphane (4.44 g, 16.9 mmol) in
THF (80 mL), a solution of DMEAD (3.96 g, 16.9 mmol) in THF
(40 mL) was added dropwise at room temperature. After 2 h, the
mixture was treated with water (0.5 mL), concentrated, and then
extracted with toluene (100 mLꢂ2) and water (100 mL). The
aqueous layer was concentrated and purified by recrystallization
from a mixture of acetone/toluene (¼5/8) to give 2.85 g of 2 as
colorless powder. The organic layer was washed with water
(100 mL), brine (100 mL), dried over magnesium sulfate, concen-
trated, and mixed with hexane (100 mL). By the filtration, triphe-
nylphosphane oxide was obtained as a colorless solid (4.61 g). The
filtrate was concentrated, and purification by a short column on
silica gel (elution with 5% ethyl acetate in hexane) gave 2.97 g of 3a
as a colorless liquid (83% yield).
4.2. Preparation of di-2-methoxyethyl
hydrazinedicarboxylate (2)
A solution of hydrazine hydrate (20 g, 400 mmol) and sodium
carbonate (46.81 g, 440 mmol) in water (160 mL) and 99.5% ethanol
(100 mL) was cooled to 5 ꢀC with an ice–water bath. 2-Methoxy-
ethyl chloroformate (121.83 g, 880 mmol) was added dropwise
while keeping the temperature below 10 ꢀC. After 2 h, the mixture
was concentrated under vacuum and then treated with acetone
(400 mL) to precipitate inorganic salts. The filtrate was concen-
trated and purified by recrystallization from a mixture of acetone
(100 mL) and toluene (160 mL) to give 71.8 g of 2 as a colorless
powder (76% yield). Mp 75.0–76.5 ꢀC; IR (KBr) 1755 cmꢁ1; 1H NMR
4.6. The reaction of (S)-2-octanol and benzoic acid with
PMe3 (TMP)
To a solution of (S)-2-octanol (130 mg, 1 mmol), benzoic acid
(159 mg, 1.3 mmol), and DMEAD (159 mg, 1.3 mmol) in toluene
(1.5 mL) was added a toluene solution of trimethylphosphane
(1.0 M, 1.3 mL) at 60 ꢀC, and the resulting mixture was stirred at
the same temperature for 12 h. After cooling, the mixture was di-
luted with toluene, washed with water (ꢂ2), and then dried over
sodium sulfate. After the concentration, the concentrate contained
only 3a deduced from the 1H NMR. Purification by a short column
on silica gel (elution with 5% ethyl acetate in hexane) gave 192 mg
of a colorless liquid (82% yield).
(400 MHz, CDCl3)
d
7.02 (br s, 2H), 4.27–4.25 (m, 4H), 3.58–3.56 (m,
156.59, 70.40, 64.68,
4H), 3.49 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
58.69. Anal. Calcd for C8H16N2O6: C, 40.68; H, 6.83; N, 11.96; obsd C,
40.78; H, 7.10; N, 12.00.
4.3. Preparation of di-2-methoxyethyl azodicarboxylate
(DMEAD, 1)
To a solution of 2 (200 g, 847 mmol) and pyridine (67.2 g,
847 mmol) in toluene (2000 mL) was added N-bromosuccinimide
(165.85 g, 932 mmol) in a small portion at room temperature. After
vigorous stirring for 3 h, the reaction mixture was washed with
water (800 mLꢂ2), dried over magnesium sulfate, concentrated
under vacuum, and then purified by recrystallization from a mix-
ture of toluene (300 mL) and hexane (1500 mL) to give 168.8 g of
DMEAD as yellow prisms (85% yield). Mp 39.9–40.4 ꢀC; IR (KBr)
References and notes
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1782 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
4.51–4.49 (m, 4H), 3.66–
160.04,
3.63 (m, 4H), 3.32 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
69.45, 67.85, 58.84. Anal. Calcd for C8H14N2O6: C, 41.03; H, 6.03; N,
11.96. Found: C, 41.09; H, 6.29; N, 12.10.
4.4. The reaction of (S)-2-octanol and benzoic acid in
diethyl ether
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To a solution of (S)-2-octanol (2 g, 15.4 mmol), benzoic acid
(2.07 g, 16.9 mmol), and triphenylphosphane (4.44 g, 16.9 mmol) in
diethyl ether (80 mL), a solution of DMEAD (3.96 g, 16.9 mmol) in
diethyl ether (40 mL) was added dropwise at room temperature.
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diethyl ether (100 mL). The combined organic layer was washed with
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from the reaction mixture by the treatment with hydrogen peroxide at rt,

6114
K. Hagiya et al. / Tetrahedron 65 (2009) 6109–6114
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